Macromolecular ketoaldehydes

ABSTRACT

Methods of producing macromolecular compositions and using same are provided. The method includes preparing a resin material; forming an acetyl group on the resin material; and oxidizing the acetyl group via a one-step reaction including reacting a sulfoxide and an acid with the acetyl group to form a ketoaldehyde group. The macromolecular compositions are capable of removing an effective amount of one or more constituents from a physiological solution, such as urea during dialysis therapy.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application is a divisional of U.S. patent application Ser.No. 10/987,331 filed Nov. 12, 2004, which is a divisional of U.S. Pat.No. 6,861,473 filed on Feb. 28, 2003, the entire disclosures of whichare expressly incorporated herein by reference.

BACKGROUND

The present invention relates generally to macromolecular compositions.More specifically, the present invention relates to methods of makingand using macromolecular ketoaldehyde compositions that have chemicalbinding properties.

In general, materials are known and used to remove constituents fromfluids for a number of different applications including, for example,industrial, recreational, therapeutic, diagnostic and/or the like. Forexample, cationic polymers, anionic polymers and combinations thereofare typically used to purify a variety of different aqueous streams,such as industrial process streams, via ion exchange, flocculation orother suitable mechanism. Other materials are generally known as sorbentmaterials. The physiochemical properties of these types of materialsenable them to remove suitable types of constituents from fluid viaadsorption, absorbtion, chemisorption, chemical binding and/or othersuitable mechanisms.

In general, polymeric materials are known in the art that are capable ofremoving nitrogen-containing compounds, such as urea, creatinine,proteins, amino acids, glyco-proteins and/or other metabolic waste insolution. These types of materials contain a functional group(s) thatchemically bind with urea or other like compounds. For example, U.S.Pat. Nos. 3,933,753 and 4,012,317 disclose an alkenylaromatic polymercontaining phenylglyoxal that can function to chemically bind urea. Asdisclosed, the process for making the glyoxal-functionalized polymer, ingeneral, includes the preparation of a poly-p-vinylacetophenone. Next, aphenacyl bromide is formed. This is followed by a separate step thatincludes the oxidation of the poly-p-vinylphenacetyl halide to form thephenylglyoxal groups. See, for example, U.S. Pat. No. 3, 933, 753,columns 7 and 8.

Another example of a polymeric material capable of removing urea or thelike in solution is disclosed in U.S. Pat. No. 4,897,200. This materialincludes a tricarbonyl functionality commonly known as ninhydrin. Thegeneral formula of the polymeric material (P-ninhydrin) is shown below:

The ninhydrin-containing material may produce better urea uptake levelsas compared to, for example, the glyoxal-containing materials discussedabove. However, the ninhydrin product is expensive to make due, in part,to the numerous reaction steps necessary to carry out the reaction.

A need, therefore, exists to provide macromolecular compositions madefrom improved methods with chemical binding properties that can beeffective even under physiological conditions and that can be readilyand easily made at reduced costs, and easily adapted to existingsystems, such as therapeutic system.

SUMMARY

The present invention relates to macromolecular compositions. Inparticular, the present invention relates to improved methods of makingand using macromolecular compositions that have chemical bindingproperties. The macromolecular compositions of the present inventioninclude macromolecular ketoaldehydes that can chemically bind with oneor more suitable constituents of any suitable fluid at enhanced uptakelevels. As used herein, the term “macromolecular composition” or otherlike terms means a large molecule, such as a molecule that has amolecular weight greater than 1000 amu including, for example, syntheticpolymers, natural polymers, and/or the like.

The present invention provides processes for producing macromolecularcompositions. The macromolecular composition can include a compositionprepared via a route of suitable conversions from, for example, a(co)polymerisate of an ethylenically unsaturated compound, such as anaromatic vinyl monomer; a polycondensate, such as obtained, for example,from a Friedel Crafts reactions of aromatic compounds; a naturalmacromolecular material and modifications thereof; a macromolecularmaterial, such as carbon or other suitable macromolecular productprepared by pyrolysis; an inorganic material, such as silica, alumina,zeolite, sodium aluminum silicates or the like; or combinations thereof.For example, the preparation of macromolecular composition can result inthe formation of a resin material composed of cross-linked polystyrene.The macromolecular composition may have a relatively high internalsurface area.

The process of the present invention includes the acetylation of themacromolecular composition. This results in the formation of anacetylated macromolecular composition, such as an acetylated polystyreneresin.

Oxidation of the macromolecular composition is performed subsequent toacetylation, thus resulting in the formation of the ketoaldehyde group.In an embodiment of the present invention, the oxidation is performed ina single reaction step. This step includes mixing the acetylatedcomposition with an oxidizing solvent, such as dimethylsulfoxide and/orthe like to form a reaction mixture. An acid, such as a hydrohalic acidincluding hydrobromic acid and/or the like is added to the reactionmixture, thus converting the acetyl groups into the ketoaldehyde groups.Applicants believe that the process of the present invention results inmacromolecular ketoaldehydes with enhanced functionalization. This canfacilitate the binding capabilities of the composition with respect to,for example, anions, molecules or radicals containing heteroatoms withfree electron pairs, such as sulfur, nitrogen, oxygen, such as urea,creatinine, uric acid, β-2 microglobulin, proteins similar to β-2microglobulin, other like metabolic waste, other suitable biologicalmatter and/or other suitable constituent.

In an embodiment, the macromolecular ketoaldehydes of the presentinvention include a ketoaldehyde. Preferably, the ketoaldehyde is aphenylglyoxal. In an embodiment, the ketoaldehyde has a phenyl group andan α-ketoaldehyde group.

The macromolecular ketoaldehyde compositions of the present inventioncan be effectively utilized in a variety of different applications evenunder physiological conditions. For example, the macromolecularcompositions of the present invention can be utilized to remove ureaand/or the like from any suitable fluid at effective uptake levels. Urearemoval or removal of any nucleophile is due to the reactive bindingbetween the ketoaldehydes of the macromolecular composition and one orboth nitrogen atoms of urea or one or more nitrogen atoms associatedwith any suitable nucleophile.

This can be particularly beneficial as applied during regenerativedialysis therapy where the dialysate is regenerated prior to reuse, suchas recirculation into, through and out of a patient's peritoneal cavityduring continuous flow peritoneal dialysis. In this regard, themacromolecular compositions of the present invention can be adapted inany suitable way to remove at least a portion of urea, other suitablemetabolic waste, suitable other biological matter and the like from thedialysate prior to reuse. It should be appreciated that themacromolecular compositions of the present invention can be utilized ina variety of different and suitable applications with respect to and inaddition to dialysis therapy.

An advantage of the present invention is to provide improved methods formaking macromolecular compositions.

Another advantage of the present invention is to provide improvedmaterials, devices, apparatuses and systems that utilize macromolecularketoaldehydes made according to an embodiment of the present invention.

Yet another advantage of the present invention is to provide improvedmacromolecular phenylglyoxals that can chemically bind urea and/or thelike.

Yet still another advantage of the present invention is to provideimproved macromolecular materials that can chemically bind urea and/orthe like under physiological conditions.

A further advantage of the present invention is to provide improvedmacromolecular compositions that can remove urea and/or the like fromsolutions used during medical therapy, such as dialysis.

Additional features and advantages of the present invention aredescribed in, and will be apparent from, the following DetailedDescription of the Invention and the FIGURES.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a schematic illustration of a system including a devicecontaining a macromolecular composition according to an embodiment ofthe present invention.

DETAILED DESCRIPTION

The present invention generally relates to macromolecular compositions.More specifically, the present invention relates to methods of makingand using macromolecular compositions, such as those containingketoaldehydes with chemical binding properties.

In general, the processes of the present invention include the steps ofpreparing the macromolecular composition, such as a cross-linkedpolystyrene resin; acetylation of the macromolecular composition; andformation of a ketoaldehyde functional group via oxidation of theacetylated macromolecular composition. The oxidation step, in general,includes the formation of acetyl halide groups and subsequent oxidationthereof to form the ketoaldehyde groups (e.g., glyoxal) in a singlereaction step as detailed below. Applicants believe that the processesof the present invention can produce ketoaldehyde-functionalizedmacromolecular compositions with binding properties with respect to avariety of different constituents in solution as previously discussed.

Applicants believe that the processes of the present invention canresult in a higher concentration of active chemical binding sites whichcorrespond to the number of glyoxals on the phenyl ring of themacromolecular composition of the present invention. This can also havethe added effect of enhancing the chemical reactivity of thecompositions of the present invention with respect to removingconstituents, such as urea, from a fluid.

As previously discussed, the process steps of the present inventiongenerally can be described as follows: 1) preparation of resin material;and 2) glyoxalation of resin material. The glyoxalation includesacetylation and subsequent oxidation. It should be appreciated that theprocesses of the present invention can include any suitable number andtype of additional types of reaction steps. For example, the processesof the present invention can include alkylation of the macromolecularcomposition to provide chemical groups in addition to the ketoaldehydegroups. The additional chemical groups may effect the macromolecularcompositions to facilitate the binding properties thereof as discussedabove. It should be appreciated that glyoxalation and the addition ofthe additional chemical groups can occur in any suitable sequenceincluding, for example, during the same process step as described indetail below.

Resin Material Preparation

The present invention can include a variety of suitable resin materials.In general, the resin material can include a porous polymeric structureor non-porous polymeric structure. The pore size can range frommicroporous to macroporous in size depending on the application. In anembodiment, the resin materials are composed of a porous bead materialmade from any suitable polymer. Preferably, the resin material is madefrom cross-linked styrene, such as styrene cross-linked with a suitableamount of a cross-linking agent, such as divinylbenzene. In anembodiment, the cross-linked resin material includes about 25% or lessby weight of the cross-linking agent. It should be appreciated that anysuitable type of material can be used as the resin material. Forexample, the resin material can include a gel material. In general, thisis a polymeric material that is effectively non-porous.

The resin material of the present invention can be made in any suitableway and/or may be commercially-available. In general, cross-linkedpolystyrene beads can be made according to known processes, such assuspension polymerization. In a typical reaction, a styrene monomer,divinylbenzene and an initiator are added to a reactor containing anaqueous phase with polymeric and/or inorganic stabilizers. Ifmacroporosity is desired, a precipitant, such as an alkane, can be addedto the monomer phase. Optionally, a solvating agent, such as toluene,can be added too. Also, a linear (monomer-soluble) polymer can be used.The reactants are typically stirred and heated to an appropriatetemperature to carry out the polymerization reaction.

The resultant polymer can be characterized in a variety of suitableways. In an embodiment, the styrene content of the polymer ranges fromabout 0.01% by weight to about 99.9% by weight; and the divinylbenzenecontent (typically includes a mixture of divinylbenzene and 3-ethylstyrene) ranges from about 0% by weight to about 90% by weight.Preferably, the styrene content is higher than the divinylbenzenecontent. In an embodiment, the divinylbenzene content ranges from about0.1% by weight to about 20% by weight. Additional other monomers orpolymers in any suitable amount can be present during polymerization.For example, the polymer can include a hydrophilic monomer or itsprecursor or a hydrophobic monomer in an amount ranging from about 0 toabout 10 mole percent or greater. Depending on the application, theresin material of the present invention can include any suitable poresize, surface area and molecular weight.

Glyoxalation

As used herein, the term “glyoxalation” or other like term meansmodifying a chemical moiety to produce a glyoxal group. For example,modifying a phenyl ring to produce a phenylglyoxal.

In an embodiment, the phenyl group of the polystyrene resin is modifiedto include the glyoxal group. This can proceed via any suitable reactionmechanism, preferably acetylation via a Friedel Crafts reaction andsubsequent oxidation of the acetyl group to form the glyoxal groupattached to the phenyl ring. As detailed below, the oxidation step, inan embodiment, can produce the glyoxal group in a single reaction step.In an embodiment, this includes the formation of an acetyl halide groupand subsequent oxidation of the acetyl halide group via a reaction withany suitable oxidizing agent, such as, sulfoxide, aliphatic sulfoxidesincluding dimethyl sulfoxide and an acid, such as hydrohalic acidincluding hydrogen bromide.

Additional Processing

As previously discussed, it should be appreciated that the processes ofthe present invention are not limited to acetylation and oxidationprocessing steps but can include any suitable number and types ofadditional processing steps. For example, chemical groups in addition tothe glyoxal groups can be attached to the phenyl ring as previouslydiscussed. These additional other groups can include, for example,electron withdrawing groups, steric groups, chemical groups that candisplay both steric and electron withdrawing effects, electron donatinggroups, halogen groups, alkyl groups and/or the like discussed above.

The additional other chemical group(s) can be added to the phenyl ringin any suitable way. For example, the alkyl group(s) can be added to thephenyl ring via alkylation with a typical Friedel Crafts catalyst, aloneor in addition to other reaction steps. In general, alkyl halides areknown to alkylate benzene to produce alkyl-benzene in the presence of aLewis acid catalyst, such as ferric chloride or aluminum chloride. Alsoalkenes in the presence of, for example, hydrochloric acid,trifluoromethane sulfonic acid and a Lewis acid catalyst can be used.

The macromolecular compositions of the present invention can besterilized in any suitable manner. In an embodiment, the macromolecularcompositions can be sterilized with gamma radiation. In general, thecomposition is exposed to a suitable amount or dose of gamma radiationsufficient for sterilization purposes. In an embodiment, themacromolecular composition of the present invention is exposed to about5 Gky to about 50 Gky of gamma radiation during sterilization. It shouldbe appreciated that sterilization by gamma radiation can be carried outin any suitable way.

In an embodiment, the macromolecular compositions of the presentinvention include ketoaldehydes wherein the ketoaldehyde includes aphenyl group and an α-ketoaldehyde group. The produced compositiondisplays chemical binding properties as described below in greaterdetail. The macromolecular ketoaldehydes can include a hydrated formand/or a non-hydrated form. A general formula that represents amacromolecular phenylketoaldehyde according to an embodiment of thepresent invention is provided below as follows:

The macromolecular ketoaldehydes of the present invention caneffectively remove any suitable number, type and amount of constituentsfrom a solution, such as a physiological solution. The constituentssuitable for removal can include, anions, molecules or radicalscontaining heteroatoms with free electron pairs, such as sulfur,nitrogen and oxygen, such as urea, creatinine, uric acid, β-2microglobulin, other like metabolic waste, other suitable biologicalmatter and/or the like. It should be appreciated that the macromolecularcompositions of the present invention can chemically bind theconstituents of any suitable fluid existing in liquid phase, gaseousphase, mixed liquid and gaseous phase, supercritical systems and/or thelike.

The chemical binding properties make the macromolecular compositions ofthe present invention well suited for a variety of differentapplications subject to physiological and/or non-physiologicalconditions. In an embodiment, the macromolecular ketoaldehydes of thepresent invention can be used to remove metabolic waste, such as urea,creatinine, uric acid and/or other like uremic toxins, biologicalmatter, proteinaceous matter, and/or the like from blood and/orsolutions used to dialyze blood.

With respect to dialysis therapy, the present invention can be used in avariety of different dialysis therapies to treat kidney failure.Dialysis therapy as the term or like terms are used throughout the textis meant to include and encompass any and all forms of therapies toremove waste, toxins and excess water from the patient. The hemotherapies, such as hemodialysis, hemofiltration and hemodiafiltration,include both intermittent therapies and continuous therapies used forcontinuous renal replacement therapy (“CRRT”). The continuous therapiesinclude, for example, slow continuous ultrafiltration (“SCUF”),continuous venovenous hemofiltration (“CVVH”), continuous venovenoushemodialysis (“CVVHD”), continuous venovenous hemodiafiltration(“CVVHDF”), continuous arteriovenous hemofiltration (“CAVH”), continuousarteriovenous hemodialysis (“CAVHD”), continuous arteriovenoushemodiafiltration (“CAVHDF”), continuous ultrafiltration periodicintermittent hemodialysis or the like. The present invention can also beused during peritoneal dialysis including, for example, continuousambulatory peritoneal dialysis, automated peritoneal dialysis,continuous flow peritoneal dialysis and the like. Further, although thepresent invention, in an embodiment, can be utilized in methodsproviding a dialysis therapy for patients having chronic kidney failureor disease, it should be appreciated that the present invention can beused for acute dialysis needs, for example, in an emergency roomsetting. However, it should be appreciated that the compositions of thepresent invention can be effectively utilized with a variety ofdifferent applications, physiologic and non-physiologic, in addition todialysis.

In an embodiment, the macromolecular compositions of the presentinvention include macromolecular phenylglyoxals as previously discussed.This type of macromolecular composition includes a phenyl group and aglyoxal group attached to the phenyl group.

It should be appreciated that the glyoxal group can be attached directlyor indirectly to the phenyl ring and in any suitable position on thering. When directly attached, the α-carbon atom of the α-ketoaldehydecan be attached to a carbon atom of the phenyl ring. When indirectlyattached, the α-carbon atom of the α-ketoaldehyde is attached to thephenyl ring via a spacer group including, for example, an aliphatic, analicyclic, an aromatic, substituted or unsubstituted group, and/or thelike. In an embodiment, the spacer group includes an aliphatic with 1 to30 atoms, such as methylene (CH₂) or the like, connected to one or acombinations of other suitable chemical groups, such as methyl, ethyl,decyl, phenyl, napthyl or the like.

It should be appreciated that the macromolecular compositions andmaterials of the present invention can include a variety of otheradditional constituents in addition to the ketoaldehydes. For example,the present invention can include hydrophilic groups, ion exchanginggroups and/or the like depending on the desired application of thepresent invention, such as for ion exchanging to remove, for example,potassium, controlling the degree of acidity, increasing accessibilityin fluid systems and/or the like. To that end, there may be presentstrongly acid or weakly acid groups or salts thereof, strongly basic orweakly basic groups or salts thereof, and/or hydroxyl groups. Suchmaterials may optionally be pre-charged with, for instance,(earth)alkali(ne) metal ions, such as sodium ions, potassium ions,calcium ions, magnesium ions, chloride ions, bicarbonate ions, acetateions and/or the like.

EXAMPLES

By way of example and not limitation, the following examples areillustrative of how to make the macromolecular compositions according toan embodiment of the present invention and further illustrateexperimental testing conducted on macromolecular compositions made inaccordance with an embodiment of the present invention.

Experiment 1a

General Procedure for the Preparation of Polyvinylacetophenone fromPolystyrene-Divinylbenzene Co-Polymer Resin (0.5-80% PS/DVB, 5 μm to 1mm):

To a portion of polystyrene-divinylbenzene co-polymer resin was addeddichloroethane or other suitable solvent in a ratio of 1:20 to 1:100(w/v), which was allowed to swell for a given period of time. To themixture may be added acetyl chloride during the swelling period. Duringthe swelling the mixture may be heated to assist in swelling. Afterswelling, 1 to 10 mole equivalence to resin was added acetyl chloridefollowed by the addition of 1 to 10 mole equivalence of aluminumchloride or other suitable Friedel-Crafts reagent. The reaction washeated at 50° C. to 65° C. for 6 to 24 hours or until the evolution ofHCl gas stopped. The resin was isolated by filtration and rinsed withacetone, water, concentrated HCl, water and acetone. The resin was thendried in vacuo at 50° C. to 80° C.

Experiment 1b

General Procedure for the Preparation of Polyvinylacetophenone fromPolystyrene-Divinylbenzene Co-Polymer Resin (0.5-80% PS/DVB, 5 μm to 1mm):

To a portion of polystyrene-divinylbenzene co-polymer resin was addeddichloroethane or other suitable solvent in a ratio of 1:20 to 1:100(w/v), which was allowed to swell for a given period of time. To themixture may be added acetyl chloride during the swelling period. Thesolvent was removed from the resin, which is not dried. The resin wasadded to a solution of 1 to 10 mole equivalence of prepared acetylchloride with aluminum chloride in dichloroethane or other suitablesolvent. The reaction was heated 50° C. to 65° C. for 6 to 24 hours oruntil the evolution of HCl gas as stopped. The resin was isolated byfiltration and rinsed with acetone, water, concentrated HCl, water andacetone. The resin was then dried in vacuo at 50° C. to 80° C.

Experiment 2a General Procedure for the Preparation of α-KetoaldehydePolystyrene-Divinylbenzene Co-Polymer Resin (0.5-80% PS/DVB, 5 μm to 1mm):

To a portion of polyvinylacetophenone polystyrene-divinylbenzeneco-polymer resin was added DMSO (dimethylsulfoxide) solvent in a ratioof 1:1 to 1:100 (w/v), which was allowed to swell for a given period oftime. During swelling, the mixture may be heated to assist in swelling.After swelling, 48% HBr (See, Floyd, M. B., et al. J. Org. Chem. 1985,50, 5022-5027) was slowly added at room temperature, after which thetemperature was raised to 65° C. to 95° C. and the DMS (dimethylsulfide) was collected by distillation. After complete distillation ofDMS, the reaction was heated to 95° C. or refluxed for an additional 2to 8 hours. The resin was isolated by filtration, washed successivelywith water and acetone. The resin was then dried under vacuum at 80° C.for a minimum of 1.5 hours.

Experiment 2b General Procedure for the Preparation of α-KetoaldehydePolystyrene-Divinylbenzene Copolymer Resin (0.5-80% PS/DVB, 5 μm to 1mm):

To 12 g of a polyvinylacetophenone polystyrene-divinylbenzene co-polymerresin was added 80 mL of DMSO. Hydrobromic acid (20 mL) was then addedat room temperature under gentle stirring. The temperature was thenincreased to 85° C. for about 8 hours after which time the resin waswashed in DMSO, DMSO/acetone mixtures, acetone and water. The resin wasdried in an oven at 60° C.

Experiment 3 Urea Uptake Experiment (Batch):

α-ketoaldehyde polymer made in accordance to an embodiment of thepresent invention was added to a urea solution prepared at 60 mg/dLconcentration. The ratio of α-ketoaldehyde polymer to urea solution waskept at 1 gram of α-ketoaldehyde polymer to 100 mL of urea solution. Ingeneral, about 500 mg of α-ketoaldehyde polymer was added to 50 mL ofurea solution in a sealed pyrex bottle which is mixed for 8 hours at 37°C. The contents of the flask were allowed to cool and the ureaconcentration of the solution is then measured per Experiment 4discussed below.

Experiment 4 Measurement of Urea Per Urease Method:

Urea concentration from aqueous samples was measured according to theTALKE and SCHUBERT method (See, Talke H and Schubert G E., Klin Wschr.1965; 43:174), on a Boehringer Mannheim/Hitachi analyzer.

Experiment 5 COCHO Quantitation:

Quantitation of α-ketoaldehyde groups was determined by a knownprocedure (See, for example, U.S. Pat. No. 4,012,317; Acta Chem. Scand.,4, 892-900 (1950); and J. Am. Chem. Soc., 94, 1434-1436 (1942). Thismethod is an indirect method of measuring α-ketoaldehyde content, byfirst converting all α-ketoaldehydes into mandelic acid groups withexcess sodium hydroxide. The mmoles of mandelic acid groups isdetermined by back titration of the excess base with hydrochloric acidto pH 7 and calculating the difference between the amount of base usedand the amount titrated.

To 100 mg of resin was added 3 mL of DMSO and 3 mL of 0.5N NaOH withstirring. After 15 minutes, 10 mL of distilled water was added, followedby neutralization of the sodium hydroxide by titration with 0.1N HCl,until the solution stabilized at pH 7.

Experiment 6 General Procedure for the Alkylation of thePolystyrene-Divinylbenzene Co-Polymer Resin (0.5-80% PS/DVB, 5 μm to 1mm):

To a portion of polystyrene-divinylbenzene co-polymer resin was addeddichloroethane or other suitable solvent in a ratio of 1:1 to 1:100(w/v). To the mixture was added 0.1% to 10% nitromethane (v/v) tosolvent, followed by the alkyl halide in 0.1 mole to 10 moleequivalence. The mixture was allowed to swell for a given period oftime, followed by the addition of AlCl₃ (0.1 to 10 mole percent of theresin). The mixture was stirred for 2-4 hours with the temperatureranging from ambient to 50° C. The alkylated resin was isolated byfiltration and rinsed with solvent. Acetylation and oxidation to preparethe alkyl α-ketoaldehyde polymer was completed as in Experiments 1b and2 discussed above. Urea uptake by the resin was completed and measuredper Experiments 3 and 4 as previously discussed.

Experiment 7 α-Ketoaldehyde Polystyrene-Divinylbenzene Co-Polymer ResinBeads (3% PS/DVB, 5 μm to 1 mm Per Experiment 1a):

Acetyl chloride (10 mL), 75 mL of dichloroethane, and 10.918 g of resinbeads were combined and allowed to swell. The resin beads arecommercially available and included 3% by weight of divinylbenzene at aparticle size that ranged from 5 μm to 1 mm. The solvent and acetylchloride were filtered and the resin was combined with 100 mL ofdichloroethane, 12 mL of acetyl chloride and 15.310 g of AlCl₃. Thereaction was heated for 6 hours and the acetylated polymer beads wereisolated by filtration, washed with 500 mL of water and 200 mL ofacetone. The beads were air dried. 6.200 grams of the acetylated polymerbeads were added to 150 mL of DMSO and heated to 80° C., followed by thedropwise addition of 48% HBr. The reaction was heated for 3 hours, andthe resin isolated by filtration, rinsed with 200 mL of water and 200 mLof acetone. After air drying, urea uptake value of 47.3 mg of urea/gramof resin was obtained according to Experiments 3 and 4 discussed above.

Experiment 8 α-Ketoaldehyde Polystyrene-Divinylbenzene Co-Polymer ResinBeads (70-80% PS/DVB Per Experiment 1a):

100 g of wet polystyrene resin beads (Supelco, Amberlite XAD-4) weredried by eluting THF through the resin beads. The resin beads arecommercially available and included 70% by weight to 80% by weight ofdivinylbenzene at a particle size that ranged from 5 μm to 1 mm. Theresin beads were then rinsed with 2×150 mL portions of dichloroethane.The resin beads were swollen with 300 mL of dichloroethane and 50 mL ofacetyl chloride. The solution was decanted and 500 mL of freshdichloroethane with 100 mL of acetyl chloride were combined with theresin followed by 147.38 grams of AlCl₃. The reaction was heated to 42°C. for 48 hours. The resin beads were isolated by filtration and rinsedwith 4 L water containing 750 mL concentrated HCl over a period of 3 to5 hours. The resin was rinsed with 2 L of water followed by 1 L of DMSO.The resin beads were transferred to a reaction flask with 500 mL ofDMSO, and 200 mL of 48% HBr. The mixture was heated to reflux and mixedfor 24 hours. The resin beads were isolated by filtration, rinsed with 4L of water over 2 hours, and dried at 80° C. in vacuum for 3 hours.After drying, urea uptake value of 8.8 mg of urea/gram of resin wasobtained as performed by Experiments 3 and 4.

Experiment 9 α-Ketoaldehyde Polystyrene-Divinylbenzene Co-Polymer ResinBeads (PS/1% DVB, Per Experiment 1b):

Preparation of the polystyrene-divinylbenzene co-polymer beads wasaccomplished by placing the polymer resin beads (2.5 g) in a dry 300 mLthree necked flask with 40 mL of dichloroethane, and 15 mL of acetylchloride for 3 hours. The swelled polymer was rinsed with excessdichloroethane and isolated by filtration. To a separate dry roundbottom 300 mL flask was added 25 mL of dichloroethane, 7 g of AlCl₃, and4.5 mL of acetyl chloride. The mixture was allowed to dissolve, followedby the addition of the previously swelled resin. The mixture was allowedto react at 65 to 75° C., for 14 hours with constant stirring. The resinwas isolated by filtration, and rinsed by the following procedure. Firstwith 300 mL of dichloroethane, 400 mL of acetone, 300 mL of water, 300mL of water with 90 mL of concentrated HCl, 600-800 mL of water and afinal rinse with 150 mL of acetone. The acetylated polymer was dried invacuo. The acetylated resin was transferred into 250 mL flask with 30 mLof DMSO (dimethylsulfoxide), and soaked at 80-90° C. for 30-45 minutes.To the reaction was added 10 mL of HBr dropwise, and heated for 2 hours.The reaction was refluxed for another two hours, cooled, rinsed withDMSO, water, acetone and isolated by filtration. The α-ketoaldehydePS/1% DVB polymer beads were dried in vacuo had a urea uptake of 45 mgof urea/gram of α-ketoaldehyde polymer according to Experiments 3 and 4.

Experiment 10 Scale-up Acetylation of 1% PS/DVB Beads to ProducePolyacetophenone:

Preparation of the Polystyrene-divinylbenzene (1% PS/DVB, 75 to 150mesh) co-polymer beads was accomplished by placing the polymer resinbeads in a dry 1 L three necked flask with 600 mL of dichloroethane, 200mL of acetyl chloride, and 45 g of the polymer. After 3 hours, thepolymer resin was isolated by filtration and washed with excessdichloroethane. To a dry round bottom IL flask was added 500 mL ofdichloroethane, 146 g of AlCl₃, and 100 mL of acetyl chloride. Themixture was allowed to dissolve, followed by the addition of 100 mL ofdichloroethane at 65 to 75° C. The previously swelled resin was slowlyadded to the solution and allowed to react at 65 to 75° C., for 14 hourswith gentle stirring. The resin was isolated by filtration, and rinsedwith dichloroethane. The resin was washed and isolated by filtrationwith 600 mL of dichloroethane, excess acetone and 23% HCl solution. Thefinal water rinse was checked at neutral pH before the final rinse with500 mL of acetone.

Experiment 11 Preparation of α-Ketoaldehyde 1% PS/DVB Beads:

To a dry 2 L 3-necked round bottom flask was added 240 mL of DMSO(dimethylsulfoxide) and 16 grams of acetylated resin from Experiment 10.The reaction mixture was mixed for 45-60 minutes at 80° C. to 90° C.under gentle stirring. To the mixture was added 80 mL of 48% hydrobromicacid while distilling off dimethylsulfide for two hours. The reactionwas allowed to reflux for an additional 2 hours. The reaction wasallowed to cool and the α-ketoaldehyde 1% PS/DVB beads were isolated byfiltration, washed successively with water and acetone. The resin wasthen dried under vacuum at 80° C. for a minimum of 1.5 hours. Theα-ketoaldehyde PS/1% DVB polymer beads were dried in vacuo and had aurea uptake of 39.6 mg of urea/gram of α-ketoaldehyde polymer accordingto Experiments 3 and 4.

Experiment 12 Urea Uptake Test I:

Several polystyrene resin beads with varying amounts of DVB wereprepared according to Experiments 7, 8, and 9 with urea uptake resultsaccording to Experiments 3 and 4. The results are shown below in Table1.

TABLE 1 Urea Uptake of α-ketoaldehyde resin per experiment 12 Uptake ofUrea mmol α- in mg/g of ketoaldehyde per % DVB Experiment urea/polymergram of resin Content 8 8.8 2.45 70-80 7 20.8 3.1 3 9 47.3 3.1 3 9 455.9 1

Experiment 13 Gamma Radiation of α-Ketoaldehyde Resins:

This experiment was conducted to determine the effect of gamma radiationon urea uptake. A resin material made pursuant to an embodiment of thepresent invention was determined to have an urea uptake value of 43.8 mgof urea per gram of resin pursuant to Experiments 3 and 4. The sameresin material was exposed to about 40 Gky to about 50 Gky gammaradiation and an urea uptake value of 43.6 mg of urea per gram of resinwas obtained according to Experiments 3 and 4.

Experiment 14 Urea Uptake Test II:

To 50 mL of a 505.8 mg/dL urea solution was added 0.507 g ofα-ketoaldehyde polymer prepared similar to experiment 10. The mixturewas sealed in a pyrex bottle and heated to 50° C. with stirring for 24hours. The urea concentration was measured as per Experiment 4, and theα-ketoaldehyde polymer had a urea uptake of 109 mg of urea per gram ofα-ketoaldehyde polymer.

Experiment 15 Urea Uptake Test III:

Urea uptake by the α-ketoaldehyde polymer prepared as in Experiment 9was measured per the procedure in Examples 11 to 15 according to U.S.Pat. No. 4,012,317. 100 mg of polymer and 15 mL of an aqueous solutionof urea of concentration 1 g/L, were mixed with either a solution of0.05 molar monopotassium phosphate (pH 7) or a solution of 0.05 mol/Lsodium carbonate and bicarbonate at pH 10. The contents of the sealedbottles were mixed for 15 hours at 37° C. with samples prepared induplicate and results averaged. Urea uptake was measured per Experiment4. The results are shown below in Table 2.

TABLE 2 Urea Uptake Comparison - 1 g/L Urea Urea Mmol of uptake inα-ketoaldehyde pH of α-ketoaldehyde mg/g of per gram of urea Timepolymer polymer resin solution (hours) 1 3.2 3.3 7 2.5 1 19.8 3.3 7 15 14.0 3.3 10 2.5 1 12.8 3.3 10 15 2 7.5 3.6 10 15 1. α-ketoaldehydepolymer prepared according to Experiment 9. 2. α-ketoaldehyde polymerprepared according to example 3 of U.S. Pat. No. 4,012,317.

Experiment 16 Urea Uptake Test IV:

Urea uptake by the α-ketoaldehyde polymer prepared in Experiment 9 wasmeasured per the procedure in Example 5 from U.S. Pat. No. 4,012,317. 25mg of α-ketoaldehyde polymer was combined with 5 mL of an aqueoussolution of urea of concentration of 1 mol/l and 5 mL of solutioncontaining either 0.05 molar monopotassium phosphate (pH 7) or 5 mL of asolution of 0.05 mol/L sodium carbonate and bicarbonate at pH 10. Thecontents of the sealed pyrex bottles were mixed for 15 hours at 37° C.,filtered and washed 10 times with 20 mL aliquots of water. The resinswere then dried under vacuo. Urea in the α-ketoaldehyde polymer measuredas percent nitrogen by elemental analysis. Results in Table 3 provide acomparison of results from the α-ketoaldehyde polymer prepared in U.S.Pat. No. 4,012,317 as indicated below.

TABLE 3 Urea Uptake Comparison - 0.5 mol/L Urea Concentration % NitrogenUrea Measured mmol of α- α- uptake in in the α- ketoaldehyde pH ofketoaldehyde mg/g of ketoaldehyde per gram urea Time polymer polymerPolymer of resin solution (hours) 1 90 3.48 3.14 7 15 1 79 3.05 3.14 1015 2 17.15 2.4³ 3.6 7 15 2 30 2.87³ 3.6 10 15 1. α-ketoaldehyde polymerprepared according to Experiment 9, with a urea uptake of 47.3 mgurea/gram of polymer per Experiments 3 and 4. 2. α-ketoaldehyde polymerprepared in U.S. Pat. No. 4,012,317 according to example 3. ³PercentNitrogen Value based on urea uptake from U.S. Pat. No. 4,012,317,example 6.

As previously discussed, the present invention provides materials,devices, apparatuses and systems that can utilize macromolecularketoaldehyde compositions made pursuant to an embodiment of the presentinvention. The macromolecular compositions of the present invention areparticularly suited for removing urea or the like under physiologicalconditions, such as from solutions used during dialysis therapy. Thebinder materials of the present invention can include any suitable typeof material including, for example, a porous bead material composed ofcross-linked polystyrene that has been modified to include a phenylring, an α-ketoaldehyde group and, optionally, one or more activatingchemical groups attached to the phenyl ring in proximity to theα-ketoaldehyde group. In an embodiment, the urea binder material of thepresent invention can remove urea from a fluid, such as a dialysis fluidduring dialysis therapy.

In an embodiment, the present invention includes devices that utilizethe urea binder material made pursuant to an embodiment of the presentinvention to remove urea in solution. In general, the device 10 includesa body 12 defining an interior 14 through which a fluid can pass intothe device 10 via an inlet 16 and optionally flow out of the device viaan outlet 18 as shown in FIG. 1. The device 10 contains the urea bindermaterial 20 of the present invention in its interior 14. The device 10can contain the urea binder material in any suitable way, such as in alayered configuration. As the fluid passes through the device, the ureabinder material acts to remove urea from the fluid.

As applied, the device is particularly suited for removal of urea from adialysis solution during dialysis therapy. In an embodiment, the deviceincludes a chemical cartridge coupled in any suitable manner to apatient loop through which dialysate is circulated into, through and outof the patient during dialysis therapy, such as continuous flowperitoneal dialysis. In this regard, the device can be used to remove atherapeutically effective amount of urea from the dialysis solution asit continually passes through the device prior to circulation into,through and out of the patient. This can enhance dialysis clearance andminimize the amount of dialysis fluid necessary to maintain effectiveclearance levels during dialysis therapy. In an embodiment, the ureabinder device can remove urea from solution used during medical therapy,such as dialysis. To achieve an effective urea uptake, the device, in anembodiment, includes about 500 g or less of the macromolecular materialmade in accordance to an embodiment of the present invention.

It should be appreciated that the chemical cartridge can include anysuitable number, type and amount of materials in addition to a ureabinder material in order to enhance treatment. For example, the chemicalcartridge can include a carbon layer for removal of creatinine,β2-microglobulin and/or the like, a material layer to remove phosphateand/or the like and the urea binder material to remove urea and/or thelike.

As previously discussed, the present invention provides a system capableof removing a constituent from a fluid. The system can be applied in avariety of different applications including, for example, therapeuticand diagnostic applications. In an embodiment, the system 22 includes afluid pathway through which the fluid can flow that is coupled to thedevice 10 as discussed above and as shown in FIG. 1. The fluid pathwayat least includes an inflow fluid path 24 allowing fluid to enter thedevice. Optionally, a number of other suitable fluid pathways can becoupled to the device, such as an outflow fluid path 26 allowing thefluid to pass through and out of the device 10.

It should be understood that various changes and modifications to thepresently preferred embodiments described herein will be apparent tothose skilled in the art. Such changes and modifications can be madewithout departing from the scope of the present subject matter andwithout diminishing its intended advantages. It is therefore intendedthat all such changes and modifications be covered by the appendedclaims.

1. A macromolecular composition from about 5 μm to about 1 mm in sizecapable of removing an effective amount of one or more constituents froma solution, the macromolecular composition comprising analpha-ketoaldehyde group attached to a phenyl group formed by oxidationof an acetylated macromolecular composition via a single-step reactionthat includes reacting the acetylated macromolecular composition with asulfoxide and a hydrohalic acid thereby forming the alpha-ketoaldehydegroup, wherein an amount of the alpha-ketoaldehyde group is less than3.6 mmol of alpha-ketoaldehyde per gram of macromolecular composition.2. The macromolecular composition of claim 1 wherein the sulfoxideincludes dimethylsulfoxide and wherein the hydrohalic acid includeshydrogen bromide.
 3. The macromolecular composition of claim 1 whereinthe macromolecular composition is capable of removing an effectiveamount of constituents from a physiological solution and wherein theconstituents are selected from the group consisting of a nucleophilicmoiety, an electron-rich chemical group, a Lewis base, a Bronsted base,an anion, including halides, molecules or radicals containing one ormore heteroatoms with a free electron pair including sulfur, nitrogen,oxygen, urea, creatinine, uric acid, β-2 microglobulin, metabolic waste,proteinaceous matter, biological matter and combinations thereof.
 4. Themacromolecular composition of claim 1 wherein the macromolecularcomposition comprises a binder material that is used in a device toremove the constituents from the solution.
 5. The macromolecularcomposition of claim 4 wherein the device is a part of a system capableof removing one or more constituents from dialysate during dialysistherapy.
 6. A method of providing dialysis therapy, the methodcomprising the steps of: passing a physiological fluid through a devicewherein at least a portion of the device at least includes amacromolecular composition, the macromolecular composition comprising analpha-ketoaldehyde group attached to a phenyl group formed by oxidationof an acetylated macromolecular composition via a single-step reactionthat includes reacting the acetylated macromolecular composition with asulfoxide and a hydrohalic acid thereby forming the ketoaldehyde group;and removing one or more constituents from the physiological fluid. 7.The method of claim 6 wherein the physiological fluid includes dialysatethat has been passed from a patient to the device which is in fluidcontact with the device.
 8. The method of claim 7 wherein theconstituents are selected from the group consisting of a nucleophilicmoiety, an electron-rich chemical group, a Lewis base, a Bronsted base,an anion, including halides, molecules or radicals containing one ormore heteroatoms with a free electron pair including sulfur, nitrogen,oxygen, urea, creatinine, uric acid, β-2 microglobulin, metabolic waste,proteinaceous matter, biological matter and combinations thereof.
 9. Themethod of claim 6 wherein the sulfoxide includes dimethylsulfoxide andthe hydrohalic acid includes hydrogen bromide.